VALORACIÓN GENERAL Durante la presente década, la cober-

Osteoporosis is a heterogeneous group of metabolic bone diseases [4] and has been defined as “a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture” [5]. Although osteoporosis is characterized by low bone mass, the ratio of bone mineral to the organic matrix in osteoporosis normal, as opposed to a decreased ratio of bone mineral to the organic matrix in osteomalacia [6, 7].

In clinical practice, the measurement of bone mineral density (BMD) is the most commonly used method for osteoporosis diagnosis. BMD is most often assessed by dual energy x-ray absorptiometry (DXA or DEXA) [5, 8]. DXA measures both bone mineral content (BMC, in grams) and area (in cm2_{). An “areal” BMD (g/cm}2_{) is obtained by dividing} bone mineral content by area. This value can be converted to a T score or a Z score. A T score

compares a patient to a sex-matched, young, healthy population; it is calculated by subtracting the mean BMD of a young adult healthy population from the patient’s BMD and then dividing by the standard deviation (SD) of the reference population. A Z score compares a patient to an age-and sex-matched control population; it is calculated by subtracting the mean BMD of an age- and sex-matched control population from the patient’s BMD and then dividing by the SD of the reference population [9]. T scores are often reported in postmenopausal women and men of 50 years age and older, while Z scores are often reported in premenopausal women, men under the age of 50, and children [9]. According to the WHO definition, the diagnosis of osteoporosis is established when BMD is 2.5 SDs below the mean for normal Caucasian women (i.e. the T score is at least −2.5 SDs) [5].

However, it has been argued that the measurement of bone mass does not account for another important determinant of bone strength—bone quality [10, 11]. Bone quality is independently influenced by parameters including bone architecture, bone turnover, microdamage, and mineralization [5]. Although BMD measurement is currently the best diagnostic practice, alternative methods that can detect the deterioration in bone quality will provide significant improvement in osteoporosis prevention, diagnosis, and treatment [11].

Osteoporosis can occur as a primary disorder or as a disorder secondary to a number of systemic diseases (e.g. hyperparathyroidism) or medications (e.g. glucocorticoids) [6]. Primary osteoporosis is the most common metabolic bone disorder in adults, mostly associated with aging. There are two clinical subtypes of age-related osteoporosis: 1) Type I or postmenopausal osteoporosis, which occurs in postmenopausal women; and 2) Type II or senile osteoporosis, which is associated with the normal aging process in both men and women [4, 12]. Menopause refers to the cessation of menstruation, which occurs at ~ 48-50

years of age for healthy women. As a result, the production of ovarian hormones including estrogen is reduced [6]. The pathogenesis of postmenopausal osteoporosis will be discussed below with a focus on the current understanding of estrogen action on osteoclastic bone resorption.

4.1.2. Cellular Pathogenesis

Under normal conditions, bone undergoes constant remodeling, where resorption of the existing bone by osteoclasts is tightly coupled to formation of new bone by osteoblasts [13]. In postmenopausal osteoporosis, the rate of bone remodeling is increased, i.e. increased number of osteoclasts and bone resorption coupled with increased number of osteoblasts and bone formation. However, due to estrogen deficiency, there is an imbalance between bone resorption and bone formation, resulting in a decrease in total bone mass [4, 7].

4.1.3. Indirect Effects of Estrogen Deficiency on Bone Resorption

Since the interplay between the immune system and bone has long been noticed [14], it is no surprise that the pathogenesis of bone loss in postmenopausal osteoporosis is mainly mediated by immune cells [15, 16]. Indeed, many studies have suggested that stimulation of bone resorption in response to estrogen deficiency is largely mediated by inflammatory and osteoclastogenic cytokines, such as IL-1, IL-6, TNFα, andIL-7 [7, 15, 17, 18]. These cytokines are able to increase the production of M-CSF by osteoblasts/stromal cells and/or the ratio of RANKL to OPG, thereby upregulating osteoclastogenesis [7, 18].

Among these cytokines, TNFα and IL-7 have been shown to be the major ones. The source of TNFα in postmenopausal osteoporosis has been identified to be T cells [16]. TNFα can stimulate osteoclastogenesis by enhancing osteoblasts/stromal cells to produce more RANKL and M-CSF, and by priming osteoclast precursors to the stimulation of RANKL. Meanwhile, TNFα can inhibit osteoblast differentiation by repressing transcription factor, Runx2 [15]. A lack of estrogen results in elevated levels of circulating cytokines, such as IL-1 and TNFα, which, in turn, stimulate osteoblasts/stromal cells to release more IL-7 [17]. On one hand, IL-7 decreases Runx2 activity, and hence inhibits osteoblast function [17, 19]. On the other hand, IL-7 stimulates the expression of M-CSF and RANKL and simultaneously decreases OPG expression by osteoblasts/stromal cells. Moreover, IL-7 targets T cells to induce RANKL production [15, 17].

In summary, TNFα and IL-7 are the key mediators involved in bone lose induced by estrogen withdrawal.

4.1.4. Direct Effects of Estrogen Deficiency on Bone Resorption

The physiological effects of estrogen are mediated by two nuclear hormone receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), with the former being the major one in most target tissues [7, 18]. Estrogen receptors are also expressed in bone cells, including bone-absorbing osteoclasts and their precursors [7, 18], which indicates that the effects of estrogen on bone resorption may be mediated, at least in part, directly. However, until recently little is known regarding the direct action of estrogen on osteoclasts [18].

Using an osteoporosis mouse model, a recent publication has elegantly demonstrated that estrogen can directly induce osteoclast apoptosis [20]. To specifically disrupt ERα gene in mature osteoclasts, the authors inserted the Cre recombinase into the cathepsin K gene locus. In another word, ERα gene is selectively deleted during osteoclastogenesis. Adult female, but not male, ERΔOc/ΔOc mice displayed high bone turnover characterized by increased osteoclast numbers, increased bone formation, but decreased trabecular bone mass [20]. So these mice mimic, to a certain degree, human postmenopausal osteoporosis. However, in ERΔOc/ΔOc mice, ovariectomy did not result in trabecular bone loss or increased osteoclast numbers. In addition, estrogen administration could not rescue the osteoporotic phenotypes of these mice. These results suggest that estrogen may directly target osteoclasts to exert its osteoprotective action.

This report further demonstrated that estrogen can upregulate Fas ligand (FasL) expression in osteoclasts and thus induce apoptosis of osteoclasts having wildtype ERα , but not those lacking ERα [20]. Since Fas is also expressed by osteoclasts, it appears that estrogen can upregulate FasL expression and affect osteoclast survival through an autocrine mechanism [21]. Collectively, these data suggested that estrogen can directly induce osteoclast apoptosis via its receptor ERα in osteoclasts [21]. In contrast, a more recent article has described a paracrine mechanism in which estrogen control osteoclast life span by upregulating FasL in osteoblasts, not osteoclasts [22]. Therefore, to generate a complete picture of the extremely complex process of postmenopausal osteoporosis, more research is necessary to identify the central cellular target(s) of estrogen.